Objective: To determine whether the impact of tobacco exposure on rheumatoid arthritis (RA) risk is influenced by polymorphisms at the HLA-DRB1 and glutathione S-transferase M1 (GSTM1) loci. Methods: Subjects were participants from a case-control study nested within the Iowa Women's Health Study, a population based, prospective cohort study of postmenopausal women. Incident RA cases (n = 115) were identified and medical records reviewed to confirm RA diagnosis. Controls without RA (n = 466) were matched with RA cases by age and ethnic background. HLA-DRB1 typing classified subjects according to the presence of alleles encoding the RA "shared epitope" (SE) sequence. GSTM1 was genotyped using a multiplex polymerase chain reaction assay. Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals. Results: Strong positive associations of smoking (OR = 6.0, p = 0.004), SE positivity (OR = 4.6, p = 0.0006), and GSTM1 null genotype (OR = 3.4, p = 0.007) with risk of RA, and significant gene-environment interactions (smoking by SE interaction p = 0.034; smoking by GSTM1 interaction p = 0.047) were observed. Stratified analyses indicated that exposure to tobacco smoke primarily increased the risk of RA among subjects who lacked genetic risk factors for the disease (that is, SE negative or GSTM1 present). Conclusions: Although these findings require confirmation in other groups, the results support the importance of considering both genetic and environmental factors, and also their interaction, in studies of complex diseases like RA.